The Neuropathology Cores (NP Core) during the past 17 years have performed the dual roles of providing thorough neuropathology expertise as a service function to the Program Projects and have also tested hypotheses regarding the etiology and pathogenesis of different forms of prion protein diseases. Project 4 proposes to make single, double and triple amino acid substitutions in the chimeric MHu2M PrP construct and similar changes in a mule deer (MuD)-mouse chimeric construct to more precisely define those portions of the PrP molecule that determine the host species barrier to different prion strains and incubation. Each of the resulting transgenic mouse lines will be inoculated with four different prion. Project 3 proposes new studies directed at understanding the structure of the transmembrane type of abnormal PrP, CtmPrP, which is found in both scrapie and Gerstmann-Straussler-Scheinker type prion disease. The NP Core is well suited to support both of these projects because the neuropathological phenotype is the most useful parameter defining the host's and prion strain's roles. Project 13 proposes a novel mutational approach to identify non-Prnp genes that alter scrapie incubation time or prevent scrapie infection. The NP Core will be asked to determine the subcellular location of the gene products and the pathological effects of knocking the genes. Project 7 proposes different techniques to learn more about the three dimensional structure of PrPSc. For the latter, the NP Core's role is largely indirect; however, it is no less important because the NP Core's goal is to determine which abnormal PrP form(s) play(s) the most critical pathogenic role in the different types of prion disease. Finally, previous NP Cores have focussed solely on detection and localization of protease-resistant rPrPSc; however, two other potentially pathogenic forms of PrP have been identified in scrapie: protease sensitive sPrPSc and CtmPrP. In contrast, large amounts of CtmPrP, but not rPrPSc, is characteristically formed by mutations of the Prnp gene in the region where mutations genetically linked to Gerstmann-Straussler-Scheinker disease occur. Therefore, this Program Project provides a unique opportunity for the NP Core to better understand the roles played by the three abnormal forms of PrP in different PrP disorders.